期刊
CIRCULATION
卷 140, 期 4, 页码 270-279出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.118.038814
关键词
antihypertensive drugs; Mendelian randomization analysis
资金
- Wellcome 4i Clinical PhD Program at Imperial College London
- Deutscher Akademischer Austaus-chdienst
- Onassis Foundation
- National Institute of Health [R01 HL133786, R01 GM120523, R01 LM010685]
- Cancer Research UK [C31250/A22804]
- Medical Research Council
- Public Health England [MR/L01341X/1]
- National Institute for Health Research Imperial Biomedical Research Centre
- Imperial College Healthcare National Health Service Trust
- UK Medical Research Council
- Alzheimer's Society
- Alzheimer's Research UK (UK Dementia Research Institute)
- European Union Horizon 2020 research and innovation programme Small vessel diseases in a mechanistic perspective: Targets for Intervention (SVDs@ target) [666881]
- German Research Foundation (DFG) [EXC 1010]
- MRC [UKDRI-5001, MR/L01341X/1] Funding Source: UKRI
Background: Drug effects can be investigated through natural variation in the genes for their protein targets. The present study aimed to use this approach to explore the potential side effects and repurposing potential of antihypertensive drugs, which are among the most commonly used medications worldwide. Methods: Genetic proxies for the effect of antihypertensive drug classes were identified as variants in the genes for the corresponding targets that associated with systolic blood pressure at genome-wide significance. Mendelian randomization estimates for drug effects on coronary heart disease and stroke risk were compared with randomized, controlled trial results. A phenome-wide association study in the UK Biobank was performed to identify potential side effects and repurposing opportunities, with findings investigated in the Vanderbilt University biobank (BioVU) and in observational analysis of the UK Biobank. Results: Suitable genetic proxies for angiotensin-converting enzyme inhibitors, beta-blockers, and calcium channel blockers (CCBs) were identified. Mendelian randomization estimates for their effect on coronary heart disease and stroke risk, respectively, were comparable to results from randomized, controlled trials against placebo. A phenome-wide association study in the UK Biobank identified an association of the CCB standardized genetic risk score with increased risk of diverticulosis (odds ratio, 1.02 per standard deviation increase; 95% CI, 1.01-1.04), with a consistent estimate found in BioVU (odds ratio, 1.01; 95% CI, 1.00-1.02). Cox regression analysis of drug use in the UK Biobank suggested that this association was specific to nondihydropyridine CCBs (hazard ratio 1.49 considering thiazide diuretic agents as a comparator; 95% CI, 1.04-2.14) but not dihydropyridine CCBs (hazard ratio, 1.04; 95% CI, 0.83-1.32). Conclusions: Genetic variants can be used to explore the efficacy and side effects of antihypertensive medications. The identified potential effect of nondihydropyridine CCBs on diverticulosis risk could have clinical implications and warrants further investigation.
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